Members of the class of compounds, alpha-N-formyl heterocyclic thiosemicarbazones, have substantial antitumor activity in animals and efforts are continuing to develop compounds useful for human cancer. It has been hypothesized that the metal-binding properties of these drugs are involved in their mechanism of action. The studies proposed here are a continuation of work designed to explore the transition metal chemistry of these materials as it relates to their antitumor effects. Four interrelated areas will be investigated: (1) The cytotoxicity of metal complexes of 5-substituted-2-formylpyridine thiosemicarbazone to Ehrlich ascites cells will be studied, with the active compounds subjected to further testing. In addition, using metal-free conditions, we will focus on the nature of the cytotoxic species, ligand, and/or metal complex. (2) Structure-function correlations will be obtained to assess the influence of pyridine ring substituents upon the chemical properties of ligand and metal complexes and secondarily upon antitumor effectiveness of these materials. (3) Studies of the chemistry of the metal complexes will continue to define the range reactivity which may be involved in their interactions with cells. (4) The reaction of iron and copper complexes with tumor cells and the nature of the responses of cells to the complexes will be considered, with particular emphasis on the mode of inhibition of ribonucleoside diphosphate reductase with iron complexes. BIBLIOGRAPHIC REFERENCES: "Inhibition of Tumor Cell Transplantability by Iron and Copper Complexes of 5-Substituted 2-Formylpyridine Thiosemicarbazones," W.E. Antholine, J.M. Knight, and D.H. Petering, J. Med. Chem., 19, 339 (1976). "Reactions of Copper Complexes with Tumor Cells," D.H. Petering, in Inorganic and Nutritional Aspects of Cancer, G.N. Schrauzer, Ed., Symposium sponsored by international Association of Bioinorganic Scientists, La Jolla, California, January 1977.